US7060828B2 - Liposomal camptothecins and uses thereof - Google Patents

Liposomal camptothecins and uses thereof Download PDF

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US7060828B2
US7060828B2 US09/896,811 US89681101A US7060828B2 US 7060828 B2 US7060828 B2 US 7060828B2 US 89681101 A US89681101 A US 89681101A US 7060828 B2 US7060828 B2 US 7060828B2
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topotecan
drug
dose
lipid
liposomal
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Thomas D. Madden
Sean C. Semple
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Talon Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1277—Preparation processes; Proliposomes
    • A61K9/1278—Post-loading, e.g. by ion or pH gradient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.
  • camptothecins such as Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin; HycamtinTM), and Irinotecan, are a semi-synthetic, water soluble derivative of camptothecin, an alkaloid extracted from the stem wood of the Chinese tree Camptotheca acuminata (Wall, et al., J. Am. Chem. Soc. 88:3888–3890 (1966)). Camptothecins belong to the topoisomerase inhibitor class of antineoplastic agents, specifically inhibiting the action of the nuclear enzyme topoisomerase I which is involved in DNA replication (Hsiang, et al., Cancer Res. 48:1722–1726 (1988)).
  • topotecan exhibits a cell cycle-specific mechanism of action, acting during S-phase (DNA replication) to cause irreversible double strand breaks in DNA that ultimately lead to G2 cell cycle arrest and apoptosis.
  • the drug has a broad spectrum of activity against a range of tumor cell lines and murine allograft and human xenograft tumor models (McCabe, F. L. et al, Cancer Invest 12:308–313 (1994); Emerson, et al, Cancer Res. 55:603–609 (1995); Thompson, Biochim. Biophys.
  • topotecan has been approved for second-line therapy in ovarian and small cell lung cancer (SCLC) and is currently the focus of extensive clinical evaluation.
  • SCLC ovarian and small cell lung cancer
  • Lipid formulations of camptothecins have been proposed as therapeutic agents (see, U.S. Pat. No. 5,552,156 and PCT Publication No. WO 95/08986.
  • not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like.
  • camptothecins the field is further complicated because dose limiting toxicities in humans may be 10-fold lower than in mice (Erickson-Miller, et al., Cancer Chemother. Pharmacol. 39:467–472 (1997)).
  • camptothecins are a promising class of anti-neoplastic agents, and lipid formulations of these drugs could prove very useful.
  • lipid formulations have not provided sufficiently remarkable activity to warrant clinical advancement. It is an object of the instant invention to provide novel lipid formulated camptothecins having novel clinical utility.
  • the present invention provides improved liposomal camptothecin (e.g., topotecan) compositions having surprisingly increased clinical efficacy and decreased collateral toxicity.
  • the present invention provides methods of using such liposomal camptothecin compositions to treat neoplasia and to inhibit angiogenesis.
  • the present invention provides a liposomal camptothecin unit dosage form comprising a camptothecin dosage of from about 0.015 mg/M 2 /dose to about 1 mg/M 2 /dose and a lipid, wherein the liposomal camptothecin unit dosage form has a drug:lipid ratio (by weight) of about 0.005 to about 0.01.
  • the unit dosage form comprises a camptothecin dosage of from about 0.15 mg/M 2 /dose to about 0.5 mg/M 2 /dose.
  • the present invention provides a liposomal topotecan unit dosage form is about 0.01 mg/M 2 /dose to about mg/M 2 /dose and a lipid and having a drug:lipid ratio (by weight) of about 0.05 to about 0.2. In certain aspects, the drug:lipid ratio (by weight) is about 0.05 to about 0.15. In another aspect, the liposomal topotecan unit dosage form is about 1 mg/M 2 /dose to about 4 mg/M 2 /dose of topotecan.
  • the present invention provides liposomal topotecan unit dosage forms.
  • the lipid comprises a mixture of sphingomyelin and cholesterol, preferably at a sphingomyelin:cholesterol molar ratio of about 70:30 to about 40:45.
  • the present invention provides a liposomal camptothecin (e.g., topotecan) formulation, wherein the formulation retains greater than 50% of the camptothecin as the active lactone species after 12 hours in blood circulation. In a preferred embodiment, the formulation retains greater than 80% of the camptothecin as the active lactone species after 12 hours in blood circulation.
  • the present invention provides a lipid formulation of a camptothecin (e.g., topotecan), comprising a camptothecin, sphingomyelin, cholesterol and a divalent ionophore, such as a divalent cation ionophore.
  • the divalent ionophore is present in trace amounts. In another preferred embodiment, the ionophore is present in greater than trace amounts.
  • the present invention provides a method of treating a solid tumor in a human afflicted therewith, the method comprising administering to the human an effective amount of a liposomal camptothecin unit dosage form in a pharmaceutically acceptable carrier.
  • a liposomal camptothecin unit dosage form in a pharmaceutically acceptable carrier.
  • the solid tumor to be treated is selected from the group consisting of solid tumors of the lung, mammary, colon and prostate.
  • the method further comprises co-administration of a treatment or active agent suitable for treating neutropenia or platelet deficiency.
  • the camptothecin dosage in the liposomal camptothecin unit dosage form ranges from 0.015 mg/M 2 /dose to about 1 mg/M 2 /dose.
  • the liposomal camptothecin unit dosage form has a drug:lipid ratio (by weight) of about 0.005 to about 0.01.
  • the unit dosage form comprises a camptothecin dosage of from about 0.15 mg/M 2 /dose to about 0.5 mg/M 2 /dose.
  • a liposomal topotecan unit dosage form is used to treat the solid tumors.
  • the liposomal unit dosage form comprises a mixture of sphingomyelin and cholesterol, preferably at a spingomyelin:cholesterol ratio (by weight) of about 30:70 to about 60:40.
  • FIG. 1 Pharmacokinetics and drug leakage of topotecan encapsulated in SM/CH vesicles.
  • Topotecan was encapsulated in 100 nm SM/CH (55/45 mol/mol) vesicles using the Mg-A23187 ionophore method as described in the Example section. Topotecan was assayed by a fluorescence assay (see, the Example section) and lipid was determined through the incorporation of a lipid marker, [ 3 H]-CHE. Data points represent the mean ⁇ SD of 4 mice.
  • the SM/CH formulation prepared by the Mn-A23187 ionophore method is included in the bottom panel for comparison (from Tardi et al, Cancer Res., 2000 submitted).
  • FIG. 2 Influence of mouse strain, dose schedule and liposome-encapsulation on topotecan tolerability in mice.
  • Balb/c mice (CT-26); Single Dose (A); NCr nude mice (LX-1); Single Dose (B); NCr nude mice (MX-1); q3dx4 (C); and NCr nude mice (MX-1); q7dx3 (D).
  • FIG. 3 Efficacy of free (A) and encapsulated (B) topotecan in an intravenous L1210 murine leukemia model-single dose.
  • L1210 cells (10 5 cells in 200 ⁇ l ) were injected i.v. into the tail vein of BDF-1 mice on day 0.
  • Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection.
  • Drug administration was made via the lateral tail vein at 1 day post-tumor cell injection. Each group consisted of 8 animals. Data is from NCTEF-005.
  • FIG. 4 Efficacy of free (A) and encapsulated (B) topotecan in an intrasplenic CT-26 murine colon metastases model-single dose.
  • CT-26 cells (10 4 cells in 50 ⁇ l) were injected into the spleen of Balb/c mice on day 0.
  • Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection. Drug administration was made via the lateral tail vein at 1 day post-tumor cell injection. Each group consisted of 8 animals. Data is from NCTEF-002.
  • FIG. 5 Efficacy of free and encapsulated topotecan in subcutaneous MX-1 human breast xenografts-single dose.
  • Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection. Drug administration was made via the lateral tail vein at 11 days post-tumor cell implantation when the tumors were 100–300 mm 3 . Data points represent mean ⁇ SEM (n ⁇ 6). Data is from NCTEF-004.
  • FIG. 6 Efficacy of free and encapsulated topotecan in subcutaneous LX-1 human SCLC xenografts-single dose.
  • FIG. 7 Efficacy of free and encapsulated topotecan in subcutaneous MX-1 xenografts-q3dx4 schedule.
  • Topotecan was encapsulated in SM:CH (55:45) vesicles at a drug-to-lipid ratio of 0.10 (w/w) using the Mg-A23187 method as described in Experimental. All dilutions were made in sterile 0.9% saline immediately prior to injection.
  • FIG. 8 Efficacy of free and encapsulated topotecan in subcutaneous MX-1 xenografts-q7dx3 schedule.
  • FIG. 9 Efficacy of free and encapsulated topotecan in subcutaneous LX-1 xenografts-q7dx3 schedule.
  • topotecan hydrochloride Hydrochloride
  • sphingomyelin/cholesterol liposomes such as sphingomyelin/cholesterol (55:45) liposomes
  • the data demonstrates a dramatic increase in therapeutic index of liposome-encapsulated topotecan relative to the free drug.
  • the present invention also provides a novel range of different dosages and dosage schedules, and a variety of drug:lipid ratio formulations of liposomal camptothecins, that are useful for treating solid tumors.
  • Liposome, vesicle and liposome vesicle will be understood to indicate structures having lipid-containing membranes enclosing an aqueous interior.
  • the structures can have one or more lipid membranes unless otherwise indicated, although generally the liposomes will have only one membrane.
  • Such single-layered liposomes are referred to herein as “unilamellar.”
  • Multilayer liposomes are referred to herein as “multilamellar.”
  • the liposomes that are used in the present invention are preferably formed from lipids which when combined form relatively stable vesicles.
  • lipids which when combined form relatively stable vesicles.
  • An enormous variety of lipids are known in the art which can be used to generate such liposomes.
  • Preferred lipids include, but are not limited to, neutral and negatively charged phospholipids or sphingolipids and sterols, such as cholesterol.
  • the selection of lipids is generally guided by consideration of, e.g., liposome size and stability of the liposomes in the bloodstream.
  • Preferred liposome compositions for use in the present invention include those comprising sphingomyelin and cholesterol.
  • the ratio of sphingomyelin to cholesterol in the liposome composition can vary, but generally is in the range of from about 75/25 mol %/mol % sphingomyelin/cholesterol to about 30/50 mol %/mol % sphingomyelin/cholesterol, more preferably about 70/30 mol %/mol % sphingomyelin/cholesterol to about 40/45 mol %/mol % sphingomyelin/cholesterol, and even more preferably about 55/45 mol %/mol % sphingomyelin/cholesterol.
  • lipids can be included in the liposome compositions of the present invention as may be necessary, such as to prevent lipid oxidation or to attach ligands onto the liposome surface. Generally, if lipids are included, the other inclusion of such lipids will result in a decrease in the sphingomyelin/cholesterol ratio. Liposomes of this type are known as sphingosomes and are more fully described in U.S. Pat. No. 5,814,335, the teachings of which are incorporated herein by reference.
  • the protocol for generating liposomes generally includes: mixing of lipid components in an organic solvent; drying and reconstituting liposomes in aqueous solvent; and sizing of liposomes (such as by extrusion), all of which are well known in the art.
  • Preparation of liposomal camptothecins requires loading of the drug into the liposomes. Loading can be either passive or active. Passive loading generally requires addition of the drug to the buffer at the time of the reconstitution step. This allows the drug to be trapped within the liposome interior, where it will remain if it is not lipid soluble, and if the vesicle remains intact (such methods are employed, for example, in PCT Publication No. WO 95/08986, the teachings of which are incorporated herein by reference).
  • Active loading is in many ways preferable, and a wide variety of therapeutic agents can be loaded into liposomes with encapsulation efficiencies approaching 100% by using a transmembrane pH or ion gradient (see, Mayer, et al., Biochim. Biophys. Acta 1025:143–151 (1990) and Madden, et al., Chem. Phys. Lipids 53:37–46 (1990)).
  • Numerous ways of active loading are known to those of skill in the art. All such methods involve the establishment of some form of gradient that draws lipophilic compounds into the interior of liposomes where they can reside for as long as the gradient is maintained. Very high quantities of the desired drug can be obtained in the interior, so much that the drug may precipitate out on the interior and generate a continuing uptake gradient.
  • ionophore mediated loading as disclosed and claimed in U.S. Pat. No. 5,837,282, the teachings of which are incorporated by reference herein.
  • this method employs an ionophore in the liposome membrane to drive the generation of a pH gradient from a previously existing monovalent or divalent ion gradient.
  • Drug:lipid ratios can be established in two ways: 1) using homogenous liposomes each containing the same drug:lipid ratio; or 2) by mixing empty liposomes with liposomes having a high drug:lipid ratio to provide a suitable average drug:lipid ratio. For different applications, different drug:lipid ratios may be desired. Techniques for generating specific drug:lipid ratios are well known in the art. Drug:lipid ratios can be measured on a weight to weight basis, a mole to mole basis or any other designated basis. Preferred drug:lipid ratios range from about 0.005 drug:lipid (by weight) to about 0.2 drug:lipid (by weight) and, more preferably, from about 0.01 drug:lipid (by weight) to about 0.02 drug:lipid (by weight).
  • a further important characteristic is the size of the liposome particles.
  • liposomes having a size of from about 0.05 microns to about 0.15 microns are preferred.
  • the present invention also provides liposomal camptothecin compositions in kit form.
  • the kit can comprise a ready-made formulation, or a formulation which requires mixing of the medicament before administration.
  • the kit will typically comprise a container that is compartmentalized for holding the various elements of the kit.
  • the kit will contain the liposomal compositions of the present invention or the components thereof, possibly in dehydrated form, with instructions for their rehydration and administration
  • the liposome compositions prepared, for example, by the methods described herein can be administered either alone or in a mixture with a physiologically-acceptable carrier (such as physiological saline or phosphate buffer) selected in accordance with the route of administration and standard pharmaceutical practice.
  • a physiologically-acceptable carrier such as physiological saline or phosphate buffer
  • suitable carriers include, e.g., water, buffered water, 0.4% saline, 0.3% glycine, and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc.
  • These compositions may be sterilized by conventional, well known sterilization techniques.
  • compositions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • the compositions may also contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
  • the composition may include lipid-protective agents which protect lipids against free-radical and lipid-peroxidative damages on storage. Lipophilic free-radical quenchers, such as ⁇ .-tocopherol and water-soluble iron-specific chelators, such as ferrioxamine, are suitable.
  • Liposomal camptothecins are used, according to this invention, in the treatment of solid tumors in an animal, such as a human.
  • the examples below set out key parameters of the drug:lipid ratios, dosages of camptothecin and lipid to be administered, and preferred dose scheduling to treat different tumor types.
  • the pharmaceutical compositions are administered parenterally, i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously or intramuscularly. More preferably, the pharmaceutical compositions are administered by intravenous drip or intraperitoneally by a bolus injection.
  • the concentration of liposomes in the pharmaceutical formulations can vary widely, i.e., from less than about 0.05%, usually at or at least about 2–5% to as much as 10 to 30% by weight and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected. For example, the concentration can be increased to lower the fluid load associated with treatment.
  • liposomes composed of irritating lipids can be diluted to low concentrations to lessen inflammation at the site of administration.
  • the amount of liposomes administered will depend upon the particular camptothecin used, the disease state being treated and the judgement of the clinician, but will generally, in a human, be between about 0.01 and about 50 mg per kilogram of body weight, preferably between about 5 and about 40 mg/kg of body weight. Higher lipid doses are suitable for mice, for example, 50–120 mg/kg.
  • Dosage for the camptothecin will depend on the administrating physician's opinion based on age, weight, and condition of the patient, and the treatment schedule.
  • a recommended dose for free topotecan in Small Cell Lung Cancer is 1.5 mg/M 2 per dose, every day for 5 days, repeated every three weeks. Because of the improvements in treatment now demonstrated in the examples, below, doses of topotecan in liposomal topotecan in humans will be effective at ranges as low as from 0.015 mg/M 2 /dose and will still be tolerable at doses as high as 15 to 75 mg/M 2 /dose, depending on dose scheduling.
  • Doses may be single doses or they may be administered repeatedly every 4h, 6h, or 12h or every 1d, 2d, 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d or combination thereof.
  • Preferred scheduling may employ a cycle of treatment that is repeated every week, 2 weeks, three weeks, four weeks, five weeks or six weeks or combination thereof.
  • treatment is given once a week, with the dose typically being less than 1.5 mg/M 2 .
  • the interval regime is at least once a week. In another embodiment, interval regime is at least once every two week, or alternatively, at least once every three weeks.
  • Particularly preferred topotecan dosages and scheduling are as follows:
  • Topotecan (HycamtinTM, SmithKline Beecham) was purchased from the pharmacy at the British Columbia Cancer Agency.
  • Sphingomyelin (SM) was purchased from Avanti Polar Lipids. Sphingomyelin from Northern Lipids was used in an early study, but was less soluble in ethanol than the Avanti version.
  • Cholesterol (CH) and the divalent cation ionophore A23187 were purchased from Sigma.
  • mice Female, ICR, BDF-1 or athymic nu/nu (6–8 weeks) were purchased from Harlan-Sprague Dawley (Indianapolis, Ind.). All animals were quarantined for one week prior to use. All studies were conducted in accordance with the guidelines established by the Canadian Council on Animal Care (CCAC) and the Institutional Animal Care and User Committee (IACUC).
  • CCAC Canadian Council on Animal Care
  • IACUC Institutional Animal Care and User Committee
  • topotecan by the Mg-A23187 method.
  • Topotecan was encapsulated in SM:CH (55:45, mol/mol) liposomes using the Mg-A23187 ionophore method according to U.S. Pat. No. 5,837,282.
  • the initial drug-to-lipid ratio was 0.10 (w/w) and drug loading was typically 95–100%.
  • the external buffer consisted of 10 mM PBS, pH 7.5 and 300 mM sucrose. All formulations were analyzed with respect to particle size, drug loading efficiency, pH, and drug and lipid concentration.
  • Total topotecan in blood was determined by a fluorescence assay preceded by precipitation of plasma proteins.
  • Topotecan was quantified by spectrofluorimetry at an excitation (2.5 nm slit width) and emission wavelength (2.5 nm slit width) of 380 and 518 nm, respectively.
  • Lipid levels in plasma were determined by liquid scintillation counting of the [ 3 H]-CHE label.
  • MTD studies MTD studies were performed in the host mouse strain corresponding to each tumor model. Single dose and multidose MTD were determined by monitoring weight loss over time. The MTD was defined as the dose that resulted in 20% weight loss.
  • the L1210 murine leukemia model and the CT-26 murine colon metastases model were employed as in standard protocols.
  • Human MX-1 and LX-1 cell lines were obtained from the DCTD Tumor Repository in Frederick, MD. These cell lines were received as tumor fragments and were propagated in NCr nude mice by serial transplantation of 3 ⁇ 3 mm fragments. Experiments were not initiated until the cell lines had been through 3 passages in nude mice and the tumor lines were restarted when the passage number reached 10.
  • therapeutic index LD 50 /ED 50
  • TI MTD/MED.
  • MTD maximum tolerated dose
  • MED minimal effective dose
  • the formulations used in this study were prepared by the Mg-A23187 ionophore method. There was an initial rapid release of drug in the first 10–30 minutes after iv administration (see, FIG. 1 , bottom), followed by a more gradual release phase.
  • the t 1/2release for the Mn-A23187 and Mg-A23187 formulations were ⁇ 3 h and ⁇ 5–7 h, respectively; however, very little drug was present in either formulation at 24 h.
  • Liposomal topotecan has been shown to exhibit exceptional anti-tumor activity, even at very low drug doses (0.5 mg/kg; drug-to-lipid ratio, 0.10, wt/wt). At these drug doses and drug-to-lipid ratio, liposome elimination from the plasma is expected to be rapid. Therefore, to determine whether the pharmacokinetics of topotecan at low doses could be improved, a low drug-to-lipid ratio (0.02, wt/wt) formulation of topotecan was investigated. Interestingly, in this study, the low drug-to-lipid ratio formulation released the drug much faster than the higher drug-to-lipid ratio (0.11, wt/wt) formulation. This result was unexpected.
  • the reported LD 10 of free topotecan following a single intravenous infusion in mice is 75 mg/M 2 ( ⁇ 25 mg/kg) [HycamtinTM product monograph]; however, very little weight loss was observed at doses up to 40 mg/kg, although this was considered the MTD due to acute responses. Drug quantities were limited so doses higher than 40 mg/kg (administered over 5–10 minutes) were not pursued. It has previously been indicated that the LD 10 of free topotecan on a qdx5 schedule is 14 mg/M2/dose ( ⁇ 4.7 mg/kg/dose) (Grochow, , et al., Drug Metab. Dispos. 20:706–713 (1992)).
  • mice Toxicity.
  • humans are more sensitive than mice to myelosuppression and can only tolerate 11% of the MTD in mice (1.5 vs 14 mg/N 2 ).
  • dogs have been shown to be a much better predictor of topotecan myelosuppression in humans (Burris, et al., J. Natl. Cancer Inst. 84:1816–1820 (1992)).
  • mice should be suitable for comparing the relative myelosuppressive effects of free and liposome encapsulated topotecan.
  • L1210 Murine Leukemia The intravenous L1210 murine leukemia model has been used extensively to evaluate differential activity between free and liposome encapsulated chemotherapeutic agents and was one of the original (1955–1975) models in the in vivo NCI screen of novel chemotherapeutic agents (Plowman, et al., Human tumor xenograft models in NCI drug development. In “ Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval” (B. Teicher, Ed.), Humana Press Inc., Totowa (1997); Waud, Murine L1210 and P388 leukemias.
  • CT-26 Murine Colon Carcinoma The murine CT-26 colon cell line is useful for drug screening since it readily grows as subcutaneous solid tumors or can be administered intravenously and used as a survival model.
  • the tumor cells are administered by intrasplenic injection, followed by splenectomy, the cells seed to the liver and give rise to an experimental metastases model that more closely resembles the clinical progression of colorectal cancer.
  • the model has been used extensively and is described, for example, in detail elsewhere.
  • MX-1 Human Breast Carcinoma.
  • MX-1 is an experimental model of human breast cancer and has a reported doubling time of 3.9 days (NCI); in this study, the median doubling time was consistently 3.6–3.7 days.
  • the tumor cell line was derived from the primary tumor of a 29-year-old female with no previous history of chemotherapy and is provided by the DCTD (NCI) tumor repository as a tumor fragment that is serially passaged in nude mice. Histologically, MX-1 is a poorly differentiated mammary carcinoma with no evidence of gland formation or mucin production.
  • MX-1 was one of 3 xenograft models (MX-1, LX-1, CX-1) that comprised the NCI in vivo tumor panel and prescreen (1976–1986) for evaluating novel chemotherapeutic agents (Plowman, et al., Human tumor xenograft models in NCI drug development. In “Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval” (B. Teicher, Ed.), Humana Press Inc., Totowa (1997)). Since then, MX-1 has been incorporated into a larger panel of breast tumor models (12 in total) to reflect a shift in NCI strategy from “compound-oriented” discovery to “disease-oriented” discovery.
  • a negative % T/C value is indicative of tumor volume regression from the original staged tumor size (100–300 mm 3 ).
  • an optimal % T/C ⁇ 10% is considered significant activity, while values ⁇ 42% are the minimum acceptable limits for advancing a drug further in development (Corbett, T. et al., In vivo methods for screening and preclinical testing. In “Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval” (B. Teicher, Ed.), Humana Press Inc., Totowa (1997)).
  • Liposome encapsulation increased the toxicity of topotecan, reducing the MTD to 10 mg/kg from>40 mg/kg for free topotecan.
  • LX-1 Human Lung Carcinoma.
  • SCLC small cell lung cancer
  • the tumor cell line was derived from the surgical explant of a metastatic lesion found in a 48 year old male and is provided by the DCTD (NCI) tumor repository as a tumor fragment that is serially passaged in nude mice.
  • NCI DCTD
  • the LX-1 model was part of the NCI in vivo tumor panel from 1976–1986 (Plowman, J. et al., Human tumor xenograft models in NCI drug development. In “Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval” (B. Teicher, Ed.), Humana Press Inc., Totowa (1997)) and, although used less frequently now, remains a useful xenograft model for comparative activity studies between free and liposomal drugs because of its rapid growth rate.
  • the LX-1 model was less sensitive to the effects of topotecan than the MX-1 model, for both free and liposome-encapsulated drug (see, FIG. 6 ; Table I).
  • Optimal % T/C values for free topotecan were 43%, 55% and 67% for doses of 30, 10 or 5 mg/kg, respectively.
  • Anti-tumor activity was improved through encapsulation, resulting in % T/C values of 8%, 11% and 13% for doses of 30, 10, or 5 mg/kg, respectively.
  • all of the liposomal topotecan doses exhibited similar activity. This was an early study and subsequent studies in other models (see, FIGS. 4–6 ) indicate dose response beginning at doses ⁇ 5 mg/kg.
  • camptothecin-class compounds can exhibit “self-limiting” efficacy whereby, at doses above a critical threshold dose, no further activity benefits are observed (Thompson, Biochim. Biophys. Acta 1400:301–319 (1998)). This situation could conceivably occur if the drug has limited tumor cell access or if the drug is acting on, and destroying, the tumor vasculature (i.e., has anti-angiogenic activity). In both instances, a higher dose of drug would be expected to have negligible benefit.
  • MX-1 Human Breast Carcinoma To address the effectiveness of multiple administration and prolonged exposure of the tumors to drug, two multiple dose protocols were examined in MX-1 xenografts—q3dx4 and q7dx3 schedules. On the q4dx3 schedule, free topotecan exhibited moderate activity at 2.5 and 10 mg/kg/dose and minimal activity at 1.25 mg/kg/dose (see, FIG. 7 ; Table II). Optimal % T/C values for free topotecan on this dosing schedule were 55%, 30% and 27% for 1.25, 2.5 and 10 mg/kg/dose, respectively.
  • optimal % T/C values were ⁇ 15%, ⁇ 100%, ⁇ 100%, and ⁇ 100% for 0.5, 1.25, 2.5 and 5 mg/kg/dose, respectively. All regressed tumors were monitored for 60 days. At the end of this period, all animals treated with ⁇ 1.25 mg/kg/dose of liposomal topotecan were considered tumor free.
  • LX-1 Human Lung Carcinoma Initial studies (single dose) in the LX-1 model indicated that free topotecan was inactive at evaluated doses ⁇ 30 mg/kg and liposomal topotecan inhibited tumor growth, but did not induce regression. To improve this activity, a multiple (q7dx3) schedule was examined for both free and liposomal topotecan. In this instance, considerably greater activity was observed for free topotecan compared to the single dose study and optimal % T/C values of 5 and 40 were obtained for 30 and 10 mg/kg/dose, respectively. Liposomal topotecan also exhibited significantly improved activity, resulting in complete regression (with subsequent re-growth) at 5 mg/kg/dose. Optimal % T/C values for liposomal topotecan in this model and dosing schedule were—55, 3 and 16 for 5, 2.5, 1.25 mg/kg/day, respectively.
  • the therapeutic index of free and liposomal topotecan was assessed in 4 different tumor models on several different dosing schedules (see, Table 4). The assumptions and definitions used to generate these numbers are found in Table III. In some instances, a true MED or MTD was not observed and was therefore estimated mathematically based on dose response trends. For instance, an acute MTD of 40 mg/kg was observed for free topotecan administered as a single bolus injection, but the true MTD (based on weight loss) would likely be closer to 60 mg/kg if the drug was infused over 5–10 minutes. Also, complicating the analysis somewhat was the level of potency of the liposomal formulation. Significant anti-tumor activity was achieved at low drug doses and the MED had to be estimated in certain studies. In these instances, a notation was made in Table 4.
  • the increase in therapeutic index for liposomal topotecan was relatively large for single dose administration (5, 10, 15 and 18-fold, depending on the model) and decreased with increasing dosing frequency. This is illustrated in Table 4, where the TI TCS /TI Free ratio was 4.7–7.5 and 3.3 for q7dx3 and q3dx4 schedules, respectively. The decrease in the TI TCS /TI Free ratio with more frequent dosing is consistent with preclinical and clinical studies indicating that the efficacy and toxicity of free topotecan is schedule-dependent.
  • a Tumor Model Route of Inoculation Dosing Schedule TI Free TI TCS TI TCS /TI Free L1210 (murine leukemia) i.v. single 1.3 (2.0) b 20 15.4 (10) b CT-26 (murine colon) i.s. single 1.0 (1.5) b 5.0 5 (3.3) b MX-1 (human breast) s.c. single 1.4 (2.1) b 25 17.9 (11.9) b q3dx4 15 50 c 3.3 q7dx3 2.0 15.0 c 7.5 LX-1 (human lung) s.c.
  • Topotecan is an excellent candidate for liposome encapsulation.
  • topotecan is cell-cycle specific (S-phase) and activity is greatly enhanced with prolonged exposure, topotecan exhibits rapid plasma pharmacokinetics and the drug needs to be maintained below pH 6.0 to retain biological activity.
  • S-phase cell-cycle specific
  • SM:CH relatively non-leaky liposome formulation
  • the required acidic interior can be produced, for example, by pH-loading or ionophore loading methodology.
  • encapsulation of topotecan in SM/CH liposomes by the Mg-A23187 method results in dramatic enhancements in anti-tumor efficacy. Modest enhancement of toxicity was also observed for liposomal topotecan, but this was largely offset by substantial dose reductions that achieved comparable and, in most instances, superior efficacy relative to the free drug.
  • Therapeutic index is a useful parameter of drug activity, as it is measure of the ratio of toxicity (MTD) to biological activity (user defined endpoint, i.e., MED, ED 50 , or ED 80 ).
  • MTD ratio of toxicity
  • Therapeutic index is particularly useful for the evaluation of liposomal drugs since the relative change in TI can be used to define the benefit (or lack thereof) of encapsulation.
  • the TI improved from 3–18 fold depending on the model and dose schedule used. Therefore, the improvement in biological activity observed following liposome encapsulation of topotecan more than compensates for any increases in toxicity.
  • Negative value indicates tumor regression.
  • b tumor growth delay difference in time for treated and control tumors to reach 500 mm 3 ).
  • c increase in lifespan relative to untreated animals (expressed as %).
  • d log cell kill gross
  • e tumor free animals at the end of study i.e. no visible tumors or long term survivors.
  • f drug related deaths g maximum mean weight loss per treatment group.
  • h positive weight change i e at no time did weight decrease below pre-treatment weight). **long term survivors
  • Negative value indicates tumor regression.
  • b tumor growth delay difference in time for treated and control tumors to reach 500 mm3.
  • c increase in lifespan relative to untreated animals (expressed as %).
  • d log cell kill gross
  • e tumor free animals at the end of study i.e. no visible tumors or long term survivors.
  • f drug related deaths g maximum mean weight loss per treatment group.
  • h positive weight change i.e. at no time did weight decrease below pre-treatment weight). i not determined; toxic deaths in the liposome-encapsulated group. **“cures”; no visible tumors by day 60.
  • DRD Drug-related death A death was considered drug-related if the animal died or was euthanized within 15 days following the final treatment with drug AND its tumor weight was less than the lethal burden on control mice, or its weight loss was greater than 20% that of the control animals.
  • GI 50 The concentration of drug that causes 50% growth inhibition in a population of cells in vitro. The NCI renamed the IC 50 parameter to emphasize the correction for cell count at time zero.
  • This parameter estimates the number of log 10 units of cells killed at the end of treatment, according to the formula: (T ⁇ C) ⁇ 0.301/median doubling time
  • Net log cell kill can be calculated by subtracting the duration of treatment from the tumor growth delay (T ⁇ C) parameter as follows: [(T ⁇ C) ⁇ duration of treatment] ⁇ 0.301/median doubling time
  • a log cell kill of 0 indicates that the cell population at the end of treatment is the same as it was at the onset of treatment. However, a log cell kill of 4, for example, indicates a 99.99% reduction in the initial cell population.
  • T/C inactive
  • % T/C > 40 1 tumor inhibition
  • % T/C range 1–40 2 tumor stasis
  • % T/C range 0 to ⁇ 40 3 tumor regression
  • % T/C range ⁇ 50 to ⁇ 100 4 % T/C range ⁇ 50 to ⁇ 100 and >30% tumor-free mice
  • TGD Tumor growth delay also represented as T ⁇ C. This parameter expresses the difference in time (in days) for treated and control tumors to attain an arbitrary size (typically 500 or 1000 mm 3 ).
  • Therapeutic index is the ratio of a toxicity parameter (i.e.
  • TI LD 50 /ED 50
  • TI MTD/MED

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CA2412795C (en) 2012-10-02
WO2002002078A2 (en) 2002-01-10
US20130136787A1 (en) 2013-05-30
MXPA02012817A (es) 2004-07-30
ATE309786T1 (de) 2005-12-15
EP1299084A2 (en) 2003-04-09
US7244448B2 (en) 2007-07-17
DE60115045D1 (de) 2005-12-22
AU2001270385B2 (en) 2006-05-25
JP2012092148A (ja) 2012-05-17
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US20110086826A1 (en) 2011-04-14
US20060269594A1 (en) 2006-11-30
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US20020119990A1 (en) 2002-08-29
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US20020110586A1 (en) 2002-08-15
IL153676A0 (en) 2003-07-06
IL153676A (en) 2007-06-17
WO2002002077A3 (en) 2002-12-12
CN1245977C (zh) 2006-03-22
EP1299084B1 (en) 2005-11-16
US20060093662A1 (en) 2006-05-04
ES2253398T3 (es) 2006-06-01
DE60115044D1 (de) 2005-12-22
US20040170678A1 (en) 2004-09-02
ATE309787T1 (de) 2005-12-15
CA2412795A1 (en) 2002-01-10
WO2002002077A2 (en) 2002-01-10
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AU2001270413A1 (en) 2002-01-14
WO2002002078A3 (en) 2002-12-27

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